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Intermittent Hypoxia Activates N-Methyl-D-Aspartate Receptors to Induce Anxiety Behaviors in a Mouse Model of Sleep-Associated Apnea

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Abstract

Sleep apnea disrupts physiologic homeostasis and causes neuronal dysfunction. In addition to signs of mental disorders and cognitive dysfunction, patients with sleep apnea have a higher anxiety rate. Here, we examined the mechanisms underlying this critical health issue. We used a mouse model with sleep-associated chronic intermittent hypoxia (IH) to verify the effects of sleep apnea on neuronal dysfunction. To evaluate how IH alters neuronal function to yield anxiety-like behavior and cognitive dysfunction, we examined synaptic plasticity and neuronal inflammation in related brain areas, including the medial prefrontal cortex (mPFC), striatum, and hippocampus. Mice subjected to chronic IH for 10 days exhibited significant anxiety-like behaviors in the elevated plus maze test. IH mice spent less travel time in open arms and more travel time in enclosed arms compared to control mice. However, cognitive impairment was minimal in IH mice. Increased glutamate N-methyl-D-aspartate (NMDA) receptor subunits 2B (GluN2B) and phosphorylated-ERK1/2 were seen in the mPFC, striatum, and hippocampus of IH mice, but no significant microglial and astrocyte activation was found in these brain areas. Chronic IH in mice induced compensatory increases in GluN2B to disturb neuronal synaptic plasticity, without neuronal inflammation. The altered synaptic plasticity subsequently led to anxiety-like behavior in mice. Treatment with the NMDA receptor antagonist dextromethorphan attenuated chronic IH-induced anxiety-like behavior and GluN2B expression. Our findings provide mechanistic evidence of how IH may provoke anxiety and support for the importance of early intervention to alleviate anxiety-associated complications in patients with chronic sleep apnea.

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Data Availability

All authors have ensured that all data and materials support the published statement and comply with field standards. The datasets generated during or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

The software (Panlab Smart video-tracking software, version 3.0, OLYMPUS cellSens Dimension version 1.13., Prism 5 and SPSS 22) that were used in this study have authorized by the original company.

References

  1. Iacono Isidoro S, Salvaggio A, Lo Bue A, Romano S, Marrone O, Insalaco G (2013) Quality of life in patients at first time visit for sleep disorders of breathing at a sleep centre. Health Qual Life Outcomes 11:207. https://doi.org/10.1186/1477-7525-11-207

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tang X, Zhang M, Zhou N, Yan J, Yang LX, Chen GH (2017) Current status of cognitive dysfunction in patients with obstructive sleep apnea hypopnea syndrome. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 31(10):813–816. https://doi.org/10.13201/j.issn.1001-1781.2017.10.022

    Article  CAS  PubMed  Google Scholar 

  3. Sharafkhaneh A, Giray N, Richardson P, Young T, Hirshkowitz M (2005) Association of psychiatric disorders and sleep apnea in a large cohort. Sleep 28(11):1405–1411. https://doi.org/10.1093/sleep/28.11.1405

    Article  PubMed  Google Scholar 

  4. Saunamaki T, Jehkonen M (2007) Depression and anxiety in obstructive sleep apnea syndrome: a review. Acta Neurol Scand 116(5):277–288. https://doi.org/10.1111/j.1600-0404.2007.00901.x

    Article  CAS  PubMed  Google Scholar 

  5. Shapiro AL, Culp S, Azulay Chertok IR (2014) OSA symptoms associated with and predictive of anxiety in middle-aged men: secondary analysis of NHANES data. Arch Psychiatr Nurs 28(3):200–205. https://doi.org/10.1016/j.apnu.2014.02.002

    Article  PubMed  Google Scholar 

  6. Amdo T, Hasaneen N, Gold MS, Gold AR (2016) Somatic syndromes, insomnia, anxiety, and stress among sleep disordered breathing patients. Sleep Breath 20(2):759–768. https://doi.org/10.1007/s11325-015-1296-6

    Article  PubMed  Google Scholar 

  7. Ringman JM, Liang LJ, Zhou Y, Vangala S, Teng E, Kremen S, Wharton D, Goate A et al (2015) Early behavioural changes in familial Alzheimer’s disease in the Dominantly Inherited Alzheimer Network. Brain 138(Pt 4):1036–1045. https://doi.org/10.1093/brain/awv004

    Article  PubMed  PubMed Central  Google Scholar 

  8. Fung AW, Chan WC, Wong CS, Chen EY, Ng RM, Lee EH, Chang WC, Hung SF et al (2017) Prevalence of anxiety disorders in community dwelling older adults in Hong Kong. Int Psychogeriatr 29(2):259–267. https://doi.org/10.1017/S1041610216001617

    Article  PubMed  Google Scholar 

  9. Fung AWT, Lee JSW, Lee ATC, Lam LCW (2018) Anxiety symptoms predicted decline in episodic memory in cognitively healthy older adults: a 3-year prospective study. Int J Geriatr Psychiatry 33(5):748–754. https://doi.org/10.1002/gps.4850

    Article  PubMed  Google Scholar 

  10. Liu S, Sun JY, Ren LP, Chen K, Xu B (2017) Propofol attenuates intermittent hypoxia induced up-regulation of proinflammatory cytokines in microglia through inhibiting the activation of NF-Bkappa/p38 MAPK signalling. Folia Neuropathol 55(2):124–131. https://doi.org/10.5114/fn.2017.68579

    Article  PubMed  Google Scholar 

  11. Yang Q, Wang Y, Feng J, Cao J, Chen B (2013) Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: the potential roles played by microglia. Neuropsychiatr Dis Treat 9:1077–1086. https://doi.org/10.2147/NDT.S49868

    Article  PubMed  PubMed Central  Google Scholar 

  12. Nair D, Dayyat EA, Zhang SX, Wang Y, Gozal D (2011) Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS One 6(5):e19847. https://doi.org/10.1371/journal.pone.0019847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Boyce-Rustay JM, Holmes A (2006) Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31(11):2405–2414. https://doi.org/10.1038/sj.npp.1301039

    Article  CAS  PubMed  Google Scholar 

  14. Sun H, Jia N, Guan L, Su Q, Wang D, Li H, Zhu Z (2013) Involvement of NR1, NR2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring. Behav Brain Res 257:1–7. https://doi.org/10.1016/j.bbr.2013.08.044

    Article  CAS  PubMed  Google Scholar 

  15. Delawary M, Tezuka T, Kiyama Y, Yokoyama K, Inoue T, Hattori S, Hashimoto R, Umemori H et al (2010) NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala. Mol Brain 3(1):37. https://doi.org/10.1186/1756-6606-3-37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Polotsky VY, Rubin AE, Balbir A, Dean T, Smith PL, Schwartz AR, O'Donnell CP (2006) Intermittent hypoxia causes REM sleep deficits and decreases EEG delta power in NREM sleep in the C57BL/6 J mouse. Sleep Med 7(1):7–16. https://doi.org/10.1016/j.sleep.2005.06.006

    Article  PubMed  Google Scholar 

  17. Nair D, Ramesh V, Li RC, Schally AV, Gozal D (2013) Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse. J Neurochem 127(4):531–540. https://doi.org/10.1111/jnc.12360

    Article  CAS  PubMed  Google Scholar 

  18. Xu W, Chi L, Row BW, Xu R, Ke Y, Xu B, Luo C, Kheirandish L et al (2004) Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience 126(2):313–323. https://doi.org/10.1016/j.neuroscience.2004.03.055

    Article  CAS  PubMed  Google Scholar 

  19. Edlund MJ, McNamara ME, Millman RP (1991) Sleep apnea and panic attacks. Compr Psychiatry 32(2):130–132. https://doi.org/10.1016/0010-440x(91)90004-v

    Article  CAS  PubMed  Google Scholar 

  20. Su VY, Chen YT, Lin WC, Wu LA, Chang SC, Perng DW, Su WJ, Chen YM et al (2015) Sleep apnea and risk of panic disorder. Ann Fam Med 13(4):325–330. https://doi.org/10.1370/afm.1815

    Article  PubMed  PubMed Central  Google Scholar 

  21. Diaz SV, Brown LK (2016) Relationships between obstructive sleep apnea and anxiety. Curr Opin Pulm Med 22(6):563–569. https://doi.org/10.1097/MCP.0000000000000326

  22. Rezaeitalab F, Moharrari F, Saberi S, Asadpour H, Rezaeetalab F (2014) The correlation of anxiety and depression with obstructive sleep apnea syndrome. J Res Med Sci 19(3):205–210

    PubMed  PubMed Central  Google Scholar 

  23. Gupta MA, Simpson FC (2015) Obstructive sleep apnea and psychiatric disorders: a systematic review. J Clin Sleep Med 11(2):165–175. https://doi.org/10.5664/jcsm.4466

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lehto SM, Sahlman J, Soini EJ, Gylling H, Vanninen E, Seppa J, Viinamaki H, Tuomilehto H (2013) The association between anxiety and the degree of illness in mild obstructive sleep apnoea. Clin Respir J 7(2):197–203. https://doi.org/10.1111/j.1752-699X.2012.00304.x

    Article  PubMed  Google Scholar 

  25. Gold MS, Amdo T, Hasaneen N, Gold AR (2016) Somatic arousal and sleepiness/fatigue among patients with sleep-disordered breathing. Sleep Breath 20(2):749–758. https://doi.org/10.1007/s11325-015-1294-8

    Article  PubMed  Google Scholar 

  26. Lee SA, Han SH, Ryu HU (2015) Anxiety and its relationship to quality of life independent of depression in patients with obstructive sleep apnea. J Psychosom Res 79(1):32–36. https://doi.org/10.1016/j.jpsychores.2015.01.012

    Article  PubMed  Google Scholar 

  27. Martinez-Garcia MA, Chiner E, Hernandez L, Cortes JP, Catalan P, Ponce S, Diaz JR, Pastor E et al (2015) Obstructive sleep apnoea in the elderly: role of continuous positive airway pressure treatment. Eur Respir J 46(1):142–151. https://doi.org/10.1183/09031936.00064214

    Article  PubMed  Google Scholar 

  28. Lago T, Davis A, Grillon C, Ernst M (2017) Striatum on the anxiety map: Small detours into adolescence. Brain Res 1654(Pt B):177–184. https://doi.org/10.1016/j.brainres.2016.06.006

    Article  CAS  PubMed  Google Scholar 

  29. Davis DM, Jacobson TK, Aliakbari S, Mizumori SJ (2005) Differential effects of estrogen on hippocampal- and striatal-dependent learning. Neurobiol Learn Mem 84(2):132–137. https://doi.org/10.1016/j.nlm.2005.06.004

    Article  CAS  PubMed  Google Scholar 

  30. Calhoon GG, Tye KM (2015) Resolving the neural circuits of anxiety. Nat Neurosci 18(10):1394–1404. https://doi.org/10.1038/nn.4101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ben Simon E, Rossi A, Harvey AG, Walker MP (2020) Overanxious and underslept. Nat Hum Behav 4(1):100–110. https://doi.org/10.1038/s41562-019-0754-8

    Article  PubMed  Google Scholar 

  32. Klumpers F, Kroes MC, Heitland I, Everaerd D, Akkermans SE, Oosting RS, van Wingen G, Franke B et al (2015) Dorsomedial prefrontal cortex mediates the impact of serotonin transporter linked polymorphic region genotype on anticipatory threat reactions. Biol Psychiatry 78(8):582–589. https://doi.org/10.1016/j.biopsych.2014.07.034

    Article  CAS  PubMed  Google Scholar 

  33. Balsara R, Dang A, Donahue D, Snow T, Castellino F (2015) Conantokin-G attenuates detrimental effects of NMDAR hyperactivity in an ischemic rat model of stroke. PLOS ONE 10:e0122840. https://doi.org/10.1371/journal.pone.0122840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu Y, Ji ES, Xiang S, Tamisier R, Tong J, Huang J, Weiss JW (2009) Exposure to cyclic intermittent hypoxia increases expression of functional NMDA receptors in the rat carotid body. J Appl Physiol (1985) 106(1):259–267. https://doi.org/10.1152/japplphysiol.90626.2008

    Article  CAS  Google Scholar 

  35. Coleman CG, Wang G, Park L, Anrather J, Delagrammatikas GJ, Chan J, Zhou J, Iadecola C et al (2010) Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus. J Neurosci 30(36):12103–12112. https://doi.org/10.1523/JNEUROSCI.3367-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG (2000) Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 3(7):661–669. https://doi.org/10.1038/76615

    Article  CAS  PubMed  Google Scholar 

  37. Sheng M, Kim MJ (2002) Postsynaptic signaling and plasticity mechanisms. Science 298(5594):776–780. https://doi.org/10.1126/science.1075333

    Article  CAS  PubMed  Google Scholar 

  38. Netzer R, Pflimlin P, Trube G (1993) Dextromethorphan blocks N-methyl-D-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons. Eur J Pharmacol 238(2-3):209–216

    Article  CAS  Google Scholar 

  39. Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR (2016) Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (Nuedexta(R)) clinical use. Pharmacol Ther 164:170–182. https://doi.org/10.1016/j.pharmthera.2016.04.010

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Rebecca Bartow, PhD, of the Department of Scientific Publications at the Texas Heart Institute, Houston, Texas, for editorial assistance.

Funding

This study was supported by grant M109108 (to SLC) from Kaohsiung Medical University and the grants #105-2628-B-037-003-MY3 (to SLC) and #107-2321-B-037-002 (to CKL) from the Taiwan Ministry of Science and Technology.

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Author notes

  1. Yun Fan and Mei-Chuan Chou contributed equally to this work.

Authors and Affiliations

  1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University (KMU), No.100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung City 807, Taiwan, Republic of China

    Yun Fan, Chu-Huang Chen & Shiou-Lan Chen

  2. Graduate Institute of Clinical Medicine, College of Medicine, KMU, Kaohsiung, Taiwan, Republic of China

    Mei-Chuan Chou

  3. Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, KMU, Kaohsiung, Taiwan, Republic of China

    Mei-Chuan Chou

  4. Department of Anesthesiology, College of Medicine, National Cheng Kung University Hospital (NCKU), Tainan, Taiwan, Republic of China

    Yen-Chin Liu

  5. Department of Neurology, KMU Hospital, Kaohsiung, Taiwan, Republic of China

    Mei-Chuan Chou & Ching-Kuan Liu

  6. Department of Neurology, Faculty of Medicine, College of Medicine, KMU, Kaohsiung, Taiwan, Republic of China

    Ching-Kuan Liu

  7. Vascular and Medicinal Research, Texas Heart Institute, Houston, TX, USA

    Chu-Huang Chen

  8. Department of Medical Research, KMU Hospital, Drug Development and Value Creation Research Center & MSc Program in Tropical Medicine, College of Medicine, KMU, Kaohsiung, Taiwan, Republic of China

    Shiou-Lan Chen

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Contributions

Yun Fa and Mei-Chuan Chou performed most of the experiments; Yen-Chin Liu, Ching-Kuan Liu, and Chu-Huang Chen helped with the parts of the experiments and revised the manuscript; Yun Fa, Mei-Chuan Chou, and Shiou-Lan Chen designed the study, analyzed the data, and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shiou-Lan Chen.

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All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Kaohsiung Medical University and carried out in accordance with AAALAC regulations, the US Department of Agriculture Animal Welfare Act, and the Guide for the Care and Use of Laboratory Animals of the NIH.

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This study did not include the human subjects.

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This study did not include the human subjects.

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Fan, Y., Chou, MC., Liu, YC. et al. Intermittent Hypoxia Activates N-Methyl-D-Aspartate Receptors to Induce Anxiety Behaviors in a Mouse Model of Sleep-Associated Apnea. Mol Neurobiol 58, 3238–3251 (2021). https://doi.org/10.1007/s12035-021-02321-0

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